tbuckley/cabot-search huggingface dataset:
Developing high-affinity decoy receptors to treat multiple myeloma and diffuse large B cell lymphoma
Authors: Yu Rebecca Miao, Kaushik Thakkar, Can Cenik, Dadi Jiang, Kazue Mizuno, Chenjun Jia, Caiyun Grace Li, Hongjuan Zhao, Anh Diep, Yu Xu, Xin Eric Zhang, Teddy Tat Chi Yang, Michaela Liedtke, Parveen Abidi, Wing-sze Leung, Albert C. Koong, Amato J. Giaccia
Journal: The Journal of Experimental Medicine (2022)

Disease relapse and treatment-induced immunotoxicity pose significant clinical challenges for patients with hematological cancers. Here, we reveal distinctive requirements for neutralizing TNF receptor ligands APRIL and BAFF and their receptor activity in MM and DLBCL, impacting protein translation and production in MM cells and modulating the translation efficiency of the ATM interactor (ATMIN/ACSIZ). Therapeutically, we investigated the use of BCMA decoy receptor (sBCMA-Fc) as an inhibitor of APRIL and BAFF. While wild-type sBCMA-Fc effectively blocked APRIL signaling in MM, it lacked activity in DLBCL due to its weak BAFF binding. To expand the therapeutic utility of sBCMA-Fc, we engineered an affinity-enhanced mutant sBCMA-Fc fusion molecule (sBCMA-Fc V3) 4- and 500-fold stronger in binding to APRIL and BAFF, respectively. The mutant sBCMA-Fc V3 clone significantly enhanced antitumor activity against both MM and DLBCL. Importantly, we also demonstrated an adequate toxicity profile and on-target mechanism of action in nonhuman primate studies.
Correction: Innate immune mediator, Interleukin-1 receptor accessory protein (IL1RAP), is expressed and pro-tumorigenic in pancreatic cancer
Authors: Yang Zhang, Xiaoyi Chen, Huamin Wang, Shanisha Gordon-Mitchell, Srabani Sahu, Tushar D. Bhagat, Gaurav Choudhary, Srinivas Aluri, Kith Pradhan, Plabani Sahu, Milagros Carbajal, Hui Zhang, Beamon Agarwal, Aditi Shastri, Robert Martell, Daniel Starczynowski, Ulrich Steidl, Anirban Maitra, Amit Verma
Journal: Journal of Hematology & Oncology (2022)
Some Antioxidants May Mitigate the Risk of Dementias
Authors: Melissa Suran
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Fusion Is Not a Safeguard to Prevent Revision Surgery in Lumbar Spinal Stenosis
Authors: Ivar Magne Austevoll, Eira Ebbs
Journal: JAMA Network Open (2022)

Nils H. Ulrich, MD; Jakob M. Burgstaller, MD, DMD, PhD, EMBA; Fabio Valeri, MSc; Giuseppe Pichierri, PhD; Michael Betz, MD; Tamas F. Fekete, MD; Maria M. Wertli, MD, PhD; François Porchet, MD; Johann Steurer, MD; Mazda Farshad, MD, MPH; Lumbar Stenosis Outcome Study Group; Florian Brunner; Sebastian Winklhofer; Roman Guggenberger; Jürg Hodler; Joachim Oberle; Urs Schmid; Min Kan
The Learning Sciences Meet the Learning Health System
Authors: Susan Wlodarczyk, Gurpreet Dhaliwal
Journal: JAMA Network Open (2022)

Matthew D. McEvoy, MD; Mary Lynn Dear, PhD; Reagan Buie, MHA; David A. Edwards, MD, PhD; Tyler W. Barrett, MD, MSCI; Brian Allen, MD; Amy C. Robertson, MD, MMHC; Leslie C. Fowler, EdD; Cassandra Hennessy, MS; Bonnie M. Miller, MD, MMHC; Kim V. Garvey, PhD; Robert P. Bland III, MS; Geoffrey M. Fleming, MD, MMHC; Don Moore, PhD; Todd W. Rice, MD, MSc; Gordon R. Bernard, MD; Christopher J. Lindsell, PhD; Vanderbilt Learning Healthcare System Platform Investigators and the Vanderbilt Committee on Opioid Monitoring and Stewardship; Robert Dittus; Shon Dwyer; Robert Freundlich; Cheryl Gatto; Frank Harrell; Paul Harris; Tina Hartert; Jim Hayman; Catherine Ivory; Kevin Johnson; Ruth Kleinpell; Sunil Kripalani; Lee Ann Liska; Patrick Luther; Jay Morrison; Thomas Nantais; Mariann Piano; Jill Pulley; Kris Rehm; Russell Rothman; Matthew Semler; Robin Steaban; Consuelo Wilkins; Adam Wright; Autumn Zuckerman; Michael Costello; R. Scott Frankenfield; Alexander Hawkins; Sterling Haring; Jason Hessler; Elizabeth Huggins; Carin McAbee; Puneet Mishra; Hayley Rector; Jennifer Slayton; Irving Zamora
Reprogrammed Schwann Cells Organize into Dynamic Tracks that Promote Pancreatic Cancer Invasion
Authors: Sylvie Deborde, Laxmi Gusain, Ann Powers, Andrea Marcadis, Yasong Yu, Chun-Hao Chen, Anna Frants, Elizabeth Kao, Laura H. Tang, Efsevia Vakiani, Masataka Amisaki, Vinod P. Balachandran, Annalisa Calo, Tatiana Omelchenko, Kristjan R. Jessen, Boris Reva, Richard J. Wong
Journal: Cancer Discovery (2022)

Abstract Nerves are a component of the tumor microenvironment contributing to cancer progression, but the role of cells from nerves in facilitating cancer invasion remains poorly understood. Here we show that Schwann cells (SC) activated by cancer cells collectively function as tumor-activated Schwann cell tracks (TAST) that promote cancer cell migration and invasion. Nonmyelinating SCs form TASTs and have cell gene expression signatures that correlate with diminished survival in patients with pancreatic ductal adenocarcinoma. In TASTs, dynamic SCs form tracks that serve as cancer pathways and apply forces on cancer cells to enhance cancer motility. These SCs are activated by c-Jun, analogous to their reprogramming during nerve repair. This study reveals a mechanism of cancer cell invasion that co-opts a wound repair process and exploits the ability of SCs to collectively organize into tracks. These findings establish a novel paradigm of how cancer cells spread and reveal therapeutic opportunities. Significance: How the tumor microenvironment participates in pancreatic cancer progression is not fully understood. Here, we show that SCs are activated by cancer cells and collectively organize into tracks that dynamically enable cancer invasion in a c-Jun–dependent manner. See related commentary by Amit and Maitra, p. 2240. This article is highlighted in the In This Issue feature, p. 2221
Relation of Incident Type 1 Diabetes to Recent COVID-19 Infection: Cohort Study Using e-Health Record Linkage in Scotland
Authors: Paul M. McKeigue, Stuart McGurnaghan, Luke Blackbourn, Louise E. Bath, David A. McAllister, Thomas M. Caparrotta, Sarah H. Wild, Simon N. Wood, Diane Stockton, Helen M. Colhoun
Journal: Diabetes Care (2022)

Studies using claims databases reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection >30 days earlier was associated with an increase in the incidence of type 1 diabetes. Using exact dates of diabetes diagnosis from the national register in Scotland linked to virology laboratory data, we sought to replicate this finding.A cohort of 1,849,411 individuals aged <35 years without diabetes, including all those in Scotland who subsequently tested positive for SARS-CoV-2, was followed from 1 March 2020 to 22 November 2021. Incident type 1 diabetes was ascertained from the national registry. Using Cox regression, we tested the association of time-updated infection with incident diabetes. Trends in incidence of type 1 diabetes in the population from 2015 through 2021 were also estimated in a generalized additive model.There were 365,080 individuals who had at least one detected SARS-CoV-2 infection during follow-up and 1,074 who developed type 1 diabetes. The rate ratio for incident type 1 diabetes associated with first positive test for SARS-CoV-2 (reference category: no previous infection) was 0.86 (95% CI 0.62, 1.21) for infection >30 days earlier and 2.62 (95% CI 1.81, 3.78) for infection in the previous 30 days. However, negative and positive SARS-CoV-2 tests were more frequent in the days surrounding diabetes presentation. In those aged 0-14 years, incidence of type 1 diabetes during 2020-2021 was 20% higher than the 7-year average.Type 1 diabetes incidence in children increased during the pandemic. However, the cohort analysis suggests that SARS-CoV-2 infection itself was not the cause of this increase.
Behavioral Counseling Interventions to Promote a Healthy Diet and Physical Activity for Cardiovascular Disease Prevention in Adults Without Known Cardiovascular Disease Risk Factors
Authors: Carrie D. Patnode, Nadia Redmond, Megan O. Iacocca, Michelle Henninger
Journal: JAMA (2022)

<h3>Importance</h3> Unhealthful dietary patterns, low levels of physical activity, and high sedentary time increase the risk of cardiovascular disease. <h3>Objective</h3> To synthesize the evidence on benefits and harms of behavioral counseling interventions to promote a healthy diet and physical activity in adults without known cardiovascular disease (CVD) risk factors to inform a US Preventive Services Task Force recommendation. <h3>Data Sources</h3> MEDLINE, PsycINFO, and the Cochrane Central Register of Controlled Trials through February 2021, with ongoing surveillance through February 2022. <h3>Study Selection</h3> Randomized clinical trials (RCTs) of behavioral counseling interventions targeting improved diet, increased physical activity, or decreased sedentary time among adults without known elevated blood pressure, elevated lipid levels, or impaired fasting glucose. <h3>Data Extraction and Synthesis</h3> Independent data abstraction and study quality rating and random effects meta-analysis. <h3>Main Outcomes and Measures</h3> CVD events, CVD risk factors, diet and physical activity measures, and harms. <h3>Results</h3> One-hundred thirteen RCTs were included (N = 129 993). Three RCTs reported CVD-related outcomes: 1 study (n = 47 179) found no significant differences between groups on any CVD outcome at up to 13.4 years of follow-up; a combined analysis of the other 2 RCTs (n = 1203) found a statistically significant association of the intervention with nonfatal CVD events (hazard ratio, 0.27 [95% CI, 0.08 to 0.88]) and fatal CVD events (hazard ratio, 0.31 [95% CI, 0.11 to 0.93]) at 4 years. Diet and physical activity behavioral counseling interventions were associated with small, statistically significant reductions in continuous measures of blood pressure (systolic mean difference, −0.8 [95% CI, −1.3 to −0.3]; 23 RCTs [n = 57 079]; diastolic mean difference, −0.4 [95% CI, −0.8 to −0.0]; 24 RCTs [n = 57 148]), low-density lipoprotein cholesterol level (mean difference, 2.2 mg/dL [95% CI, −3.8 to −0.6]; 15 RCTs [n = 6350]), adiposity-related outcomes (body mass index mean difference, −0.3 [95% CI, −0.5 to −0.1]; 27 RCTs [n = 59 239]), dietary outcomes, and physical activity at 6 months to 1.5 years of follow-up vs control conditions. There was no evidence of greater harm among intervention vs control groups. <h3>Conclusions and Relevance</h3> Healthy diet and physical activity behavioral counseling interventions for persons without a known risk of CVD were associated with small but statistically significant benefits across a variety of important intermediate health outcomes and small to moderate effects on dietary and physical activity behaviors. There was limited evidence regarding the long-term health outcomes or harmful effects of these interventions.
My Father Wilts
Authors: Ellen Zhang
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Updated USPSTF Recommendations for Behavioral Counseling Interventions
Authors: Sara N. Bleich
Journal: JAMA Internal Medicine (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer
Authors: Erika Durinikova, Nicole M. Reilly, Kristi Buzo, Elisa Mariella, Rosaria Chilà, Annalisa Lorenzato, João M. L. Dias, Gaia Grasso, Federica Pisati, Simona Lamba, Giorgio Corti, Andrea Degasperi, Carlotta Cancelliere, Gianluca Mauri, Pietro Andrei, Michael Linnebacher, Silvia Marsoni, Salvatore Siena, Andrea Sartore-Bianchi, Serena Nik-Zainal, Federica Di Nicolantonio, Alberto Bardelli, Sabrina Arena
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Genomic instability is a hallmark of cancer and targeting DNA damage response (DDR) is emerging as a promising therapeutic strategy in different solid tumors. The effectiveness of targeting DDR in colorectal cancer has not been extensively explored. Experimental Design: We challenged 112 cell models recapitulating the genomic landscape of metastatic colorectal cancer with ATM, ATR, CHK1, WEE1, and DNA-PK inhibitors, in parallel with chemotherapeutic agents. We focused then on ATR inhibitors (ATRi) and, to identify putative biomarkers of response and resistance, we analyzed at multiple levels colorectal cancer models highly sensitive or resistant to these drugs. Results: We found that around 30% of colorectal cancers, including those carrying KRAS and BRAF mutations and unresponsive to targeted agents, are sensitive to at least one DDR inhibitor. By investigating potential biomarkers of response to ATRi, we found that ATRi-sensitive cells displayed reduced phospho-RPA32 foci at basal level, while ATRi-resistant cells showed increased RAD51 foci formation in response to replication stress. Lack of ATM and RAD51C expression was associated with ATRi sensitivity. Analysis of mutational signatures and HRDetect score identified a subgroup of ATRi-sensitive models. Organoids derived from patients with metastatic colorectal cancer recapitulated findings obtained in cell lines. Conclusions: In conclusion, a subset of colorectal cancers refractory to current therapies could benefit from inhibitors of DDR pathways and replication stress. A composite biomarker involving phospho-RPA32 and RAD51 foci, lack of ATM and RAD51C expression, as well as analysis of mutational signatures could be used to identify colorectal cancers likely to respond to ATRi.
Changes in Buprenorphine and Methadone Supplies in the US During the COVID-19 Pandemic
Authors: Annie Y. Chen, David Powell, Bradley D. Stein
Journal: JAMA Network Open (2022)

<h3>Importance</h3> The opioid crisis has been exacerbated by the COVID-19 pandemic in the US, with concerns over major disruptions to medication treatment of opioid use disorder. <h3>Objective</h3> To investigate whether the COVID-19 pandemic was associated with disruption of buprenorphine and methadone supplies in the US. <h3>Design, Setting, and Participants</h3> This repeated cross-sectional study used ARCOS (Automated Reports and Consolidated Ordering System) data, which monitor the flow of controlled substances in the US, from January 1, 2012, through June 30, 2021. Manufacturers and point of sale or distribution at the dispensing or retail level, including hospitals, retail pharmacies, clinicians, midlevel clinicians, and teaching institutions, were included in the analysis. <h3>Exposures</h3> COVID-19 pandemic. <h3>Main Outcomes and Measures</h3> Quarterly supplies of buprenorphine and methadone per capita in milligrams. <h3>Results</h3> The per capita supply of methadone dropped from 13.2 mg in the first quarter of 2020 to 10.5 mg in the second quarter of 2020, whereas the per capita supply of buprenorphine increased from 3.6 mg to 3.7 mg in the same period. The per capita supply of methadone declined 20% (−2.7 mg) in the second quarter of 2020 compared with the first quarter of 2020, and the supply had not returned to 2019 levels as of June 2021, whereas the supply of buprenorphine per person increased consistently during the same period. There were considerable state disparities in the reduction of the methadone supply during the pandemic, with many states experiencing pronounced per capita supply decreases, including reductions as great as 50% in New Hampshire and Florida. These decreases in per capita methadone supply were not compensated by proportional increases in the per capita buprenorphine supply (linear fit, 0.17 [95% CI, −0.43 to 0.76];<i>P</i>= .47). <h3>Conclusions and Relevance</h3> This cross-sectional study of buprenorphine and methadone supplies during the COVID-19 pandemic found a pronounced decline in the methadone supply but no disruption to the buprenorphine supply. Future research is needed to explain the pronounced state disparities in the methadone supply.
GMC set to lose power to appeal decisions by medical practitioners tribunals
Authors: Clare Dyer
Journal: BMJ (2022)

Anxiety and depression are disabling, underdiagnosed issues that affect the management of oncology patients. Until recently, there has been no standard protocol for screening and treating these ailments at our cancer centre. The purpose of this institutional review board-approved study was to analyse the implementation of a screening tool in our clinical workflow with the aim of screening over 90% of patients and increasing referrals to mental health services by 50%.
Identification of risk genes for Alzheimer’s disease by gene embedding
Authors: Yashwanth Lagisetty, Thomas Bourquard, Ismael Al-Ramahi, Carl Grant Mangleburg, Samantha Mota, Shirin Soleimani, Joshua M. Shulman, Juan Botas, Kwanghyuk Lee, Olivier Lichtarge
Journal: Cell Genomics (2022)

Most disease-gene association methods do not account for gene-gene interactions, even though these play a crucial role in complex, polygenic diseases like Alzheimer's disease (AD). To discover new genes whose interactions may contribute to pathology, we introduce GeneEMBED. This approach compares the functional perturbations induced in gene interaction network neighborhoods by coding variants from disease versus healthy subjects. In two independent AD cohorts of 5,169 exomes and 969 genomes, GeneEMBED identified novel candidates. These genes were differentially expressed in post mortem AD brains and modulated neurological phenotypes in mice. Four that were differentially overexpressed and modified neurodegeneration in vivo are PLEC, UTRN, TP53, and POLD1. Notably, TP53 and POLD1 are involved in DNA break repair and inhibited by approved drugs. While these data show proof of concept in AD, GeneEMBED is a general approach that should be broadly applicable to identify genes relevant to risk mechanisms and therapy of other complex diseases.
Internal Relative Potency Factors for the Risk Assessment of Mixtures of Per- and Polyfluoroalkyl Substances (PFAS) in Human Biomonitoring
Authors: Wieneke Bil, Marco J. Zeilmaker, Bas G.H. Bokkers
Journal: Environmental Health Perspectives (2022)

Background: In human biomonitoring, blood is often used as a matrix to measure exposure to per- and polyfluoroalkyl substances (PFAS). Because the toxicokinetics of a substance (determining the steady-state blood concentration) may affect the toxic potency, the difference in toxicokinetics among PFAS has to be accounted for when blood concentrations are used in mixture risk assessment. Objectives: This research focuses on deriving relative potency factors (RPFs) at the blood serum level. These RPFs can be applied to PFAS concentrations in human blood, thereby facilitating mixture risk assessment with primary input from human biomonitoring studies. Methods: Toxicokinetic models are generated for 10 PFAS to estimate the internal exposure in the male rat at the blood serum level over time. By applying dose–response modeling, these internal exposures are used to derive quantitative internal RPFs based on liver effects. Results: Internal RPFs were successfully obtained for nine PFAS. Perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoDA), perfluorooctane sulfonic acid (PFOS), and hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX) were found to be more potent than perfluorooctanoic acid (PFOA) at the blood serum level in terms of relative liver weight increase, whereas perfluorobutane sulfonic acid (PFBS) and perfluorohexane sulfonic acid (PFHxS) were found to be less potent. The practical implementation of these internal RPFs is illustrated using the National Health and Nutrition Examination Survey (NHANES) biomonitoring data of 2017–2018. Discussion: It is recommended to assess the health risk resulting from exposure to PFAS as combined, aggregate exposure to the extent feasible. https://doi.org/10.1289/EHP10009
Interleukin-21, acting beyond the immunological synapse, independently controls T follicular helper and germinal center B cells
Authors: Isaak Quast, Alexandra R Dvorscek, Celine Pattaroni, Thiago M Steiner, Craig I McKenzie, Catherine Pitt, Kristy O'Donnell, Zhoujie Ding, Danika L Hill, Robert Brink, Marcus J Robinson, Dimitra Zotos, David M Tarlinton
Journal: Immunity (2022)